COMMENTARIES

Metabolic Syndrome and Atherosclerosis: What about Femoral Involvement?

Gaetano Vaudo, M.D., Department of Clinical and Experimental Medicine, University of Perugia Medical School S. Maria della Misericordia Hospital,
Piazzale Menghini, 1
06129 Perugia
Italy
Please address correspondence to:
Gaetano Vaudo, M.D.
Associate Professor of Internal Medicine
Internal Medicine, Angiology, and Atherosclerosis Diseases
Department of Clinical and Experimental Medicine
University of Perugia Medical School
S. Maria della Misericordia Hospital
Piazzale Menghini, 1
06129 Perugia, Italy
Tel: (+39) 0755784015
Fax: (+39) 0755784021
E-mail: gvaudo@unipg.it

Gaetano Vaudo

Metabolic syndrome as defined by the presence of at least three of the following factors: high triglyceride levels, low high density lipoproteins (HDL), high fasting glycemia, hypertension, and abdominal obesity, represents a cardiovascular risk condition and is associated with increased coronary atherosclerosis [1-3]. Evidence has revealed the relationship between the early stages of atherosclerosis and the components of metabolic syndrome [4,5]. It is well established that metabolic syndrome has a predictive power on the development of carotid atherosclerosis [6,7], but less is known about femoral involvement. However, it seems that atherosclerosis starts earlier in the femoral artery compared to carotid artery [8] and patients with peripheral atherosclerotic involvement are characterized by a lipid pattern similar to metabolic syndrome [9].

          On the basis of these considerations, we investigated the association between metabolic syndrome and preclinical atherosclerosis, by the assessment of endothelial function expressed as brachial flow-mediated vasodilation (FMV) and intima-media thickening (IMT) at both carotid and femoral districts, to investigate whether this metabolic disorder may favor a different degree of atherosclerotic involvement in the vascular tree. On hundred forty-seven outpatients with metabolic syndrome were enrolled and matched versus a control group of 87 subjects. Patients had lower values of FMV and a higher mean IMT, at the carotid and femoral district, relative to controls. Analyzing patients on the basis of the number of metabolic syndrome factors (group A with 3 factors and group B with > than 3 factors), patients of group B showed a higher IMT at the internal carotid and in the femoral district. FMV had a positive correlation with HDL cholesterol, and a negative one with LDL cholesterol, glycemia, and insulinemia; carotid mean IMT was related directly to LDL cholesterol and age, inversely with HDL cholesterol; femoral mean IMT had a direct association with LDL cholesterol, triglycerides, glycemia, and insulinemia and an inverse correlation with HDL cholesterol and LDL size. LDL cholesterol, HDL cholesterol, insulin, and brachial-artery diameter were predictive of brachial FMV, while age, LDL, and HDL cholesterol were the independent predictors of mean carotid IMT and LDL cholesterol, triglycerides, and insulin were the independent predictors of mean femoral IMT.

            The negative influence of insulin resistance on endothelial function is mediated by a number of mechanisms all reducing nitric oxide levels: inhibition of phosphoinositol-3 (PI-3) kinase pathway [10], augmentation in free fatty acids [11], increased levels of proinflammatory adipokines [12], production of reactive oxygen species [13], reduced HDL with lower antioxidant and anti-inflammatory effects [14], and increased blood pressure levels [15]. Patients affected by metabolic syndrome had a higher carotid and femoral IMT. Carotid IMT seems to be modulated mainly by LDL and HDL cholesterol; however, at femoral districts IMT was associated to LDL size and HDL cholesterol and independently predicted by LDL cholesterol, triglycerides, and insulin. The relevance of LDL on intima-media thickening, along with the protective action exerted by HDL on the arterial wall, is well established [16,17]. The high susceptibility to oxidation of LDL could be explain the capacity of this lipid subfraction to penetrate into intima-media space; in fact, oxidized LDL are able to access and to deposit inside the vascular wall by mean their high affinity for proteoglycans of intima, nevertheless LDL-proteoglycan complexes show increased susceptibility to oxidation [18]. HDL cholesterol reduces the oxidative charge of LDL consequently protecting vascular surface [19].

          The relevance of lipid metabolism on the atherosclerosis at peripheral district is a controversial topic. Previous observations have been suggested that patients affected by peripheral arterial disease are characterized by low HDL cholesterol, normal levels of LDL cholesterol, and by an altered clearance of postprandial triglycerides describing a metabolic cluster indicating a potential different impact of lipid factors on vascular districts [20]. More recently, in a large cross-sectional study it has been documented that metabolic syndrome is more prevalent in patients affected by peripheral arterial disease than in patients with coronary and cerebrovascular atherosclerosis [3]. In the metabolic syndrome there is the concurrence of several mechanisms promoting atherosclerotic process such as decreased fibrinolysis, oxidative stress, small dense LDL cholesterol, and increased inflammation [21]. The demonstration of an association between intima media thickening and small dense LDL only at femoral site suggests that this vascular district is more susceptible to the oxidative charge of this lipid fraction.

          In conclusion the presence of an impaired altered endothelial function and an intima-media thickening in patients with metabolic syndrome without overt cardiovascular disease is a fact and the morphological vascular damage seems to be more relevant at femoral level.

References

  1.    Grundy SM, Cleeman JI, Merz CN, et al.; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32.
  2.    Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16.
  3.    Wilson PWF, D'agostino RB, Parise H, Sullivan L, Meigs JB Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112:3066-72.
  4.    Arcaro G, Cretti A, Balzano S, et al. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002;105:576-82.
  5.    Thomas GN, Chook P, Qiao M, et al. Deleterious impact of "high normal" glucose levels and other metabolic syndrome components on arterial endothelial function and intima-media thickness in apparently healthy Chinese subjects: the CATHAY study. Arterioscler Thromb Vasc Biol 2004;24:739-43.
  6.    Wallenfeldt K, Bokemark L, Wikstrand J, Hulthe J, Fagerberg B. Apolipoprotein B/apolipoprotein A-I in relation to the metabolic syndrome and change in carotid artery intima-media thickness during 3 years in middle-aged men. Stroke 2004;35:2248-52.
  7.    Scuteri A, Najjar SS, Muller DC, et al. Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness. J Am Coll Cardiol 2004;43:1388-95.
  8.    Kroger K, Kucharczik A, Hirche H, Rudofsky G. Atherosclerotic lesions are more frequent in femoral arteries than in carotid arteries independent of increasing number of risk factors. Angiology 1999;50:649-54.
  9.    Mowat BF, Skinner ER, Wilson HM, Leng GC, Fowkes FG, Horrobin D. Alterations in plasma lipids, lipoproteins and high density lipoprotein subfractions in peripheral arterial disease. Atherosclerosis 1997;131:161-66.
  10.    Klafter R, Arbiser JL. Regulation of angiogenesis and tumorigenesis by signal transduction cascades: lessons from benign and malignant endothelial tumors. J Investig Dermatol Symp Proc 2000;5:79-82.
  11.    Wyne KL. Free fatty acids and type 2 diabetes mellitus. Am J Med 2003;115 Suppl 8A:29S-36S.
  12.    Aldhahi W, Hamdy O. Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 2003;3:293-98.
  13.    Clapp BR, Hingorani AD, Kharbanda RK, et al. Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res 2004;64:172-78.
  14.    Lassegue B, Griendling KK. Reactive oxygen species in hypertension; An update. Am J Hypertens 2004;17:852-60.
  15.    Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS; Bogalusa Heart Study. Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study). Am J Cardiol 2002;90:953-58.
  16.    Liu ML, Ylitalo K, Salonen R, Salonen JT, Taskinen MR. Circulating oxidized low-density lipoprotein and its association with carotid intima-media thickness in asymptomatic members of familial combined hyperlipidemia families. Arterioscler Thromb Vasc Biol 2004;24:1492-97.
  17.    Calabresi L, Gomaraschi M, Franceschini G. Endothelial protection by high-density lipoproteins: from bench to bedside. Arterioscler Thromb Vasc Biol 2003;23:1724-31.
  18.    Fukuchi M, Watanabe J, Kumagai K, et al. Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. Lab Invest 2002;82:1437-47.
  19.    Hansel B, Giral P, Nobecourt E, et al. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab 2004;89:4963-71.
  20.    Newall RG, Bliss BP. Lipoproteins and the relative importance of plasma cholesterol and triglycerides in peripheral arterial disease. Angiology 1973;24:297-302.
  21.    Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation 2004;109(23 Suppl.1):III2-7.

 

 

CLOSE THE WINDOW